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GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Disease characteristics. Alpha1-antitrypsin deficiency (α1ATD, AATD) caused by homozygosity for the common deficiency allele, PI*Z, is characterized by chronic obstructive pulmonary disease (COPD) in adults and liver disease in children and adults. COPD, specifically emphysema, is the most common manifestation of AATD. Smoking is the major factor influencing the course of COPD. The onset of respiratory disease in smokers with AATD is between age 40 and 50 years; in non-smokers, the onset can be delayed to the sixth decade. Non-smokers often have a normal life span. Although reported, emphysema in children with AATD is extremely rare. AATD-associated liver disease, present in only a small portion of affected children, is manifest as obstructive jaundice and raised serum aminotransferase levels in the early days and months of life. The incidence of liver disease increases with age; liver disease in adults, manifest as cirrhosis and fibrosis, is not necessarily associated with a history of neonatal liver disease. Hepatocellular carcinoma (HCC) has been reported. Clinical disease is infrequent in heterozygotes, except in some smokers.
Diagnosis/testing. The diagnosis of AATD relies on demonstration of low plasma concentration of alpha1-antitrypsin (AAT) and either observation of a deficient variant of the protein AAT by protease inhibitor (PI) typing or detection of mutations in both copies of the gene SERPINA1, which encodes AAT. PI*Z (resulting from the mutation p.E342K) is the most common deficiency allele. Ninety-five percent of AATD results from the presence of two Z alleles. Molecular genetic testing is clinically available.
Management. Intravenous augmentation therapy (regular infusion of purified human AAT to augment deficient ATT serum concentrations) has been recommended for affected individuals whose FEV1 is 35%-50% of predicted and who have quit smoking yet continue to show rapid decline in FEV1 despite optimal medical therapy; however, appropriately controlled trials have not been carried out. Avoidance of smoking (both personal and passive), occupations with exposure to environmental pollutants, and exposure to mineral dust, gas, and fumes is recommended. Liver transplantation, the preferred surgical treatment for advanced liver disease, can provide a cure because the donor liver produces AAT.
Genetic counseling. AATD is inherited in an autosomal recessive manner. When both parents are heterozygotes, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. In the rare instance in which one parent is homozygous (PI ZZ) and one parent is heterozygous, the risk to each sib of being affected is 50%. Unless an individual with AATD has children with a reproductive partner who is affected or a carrier, his/her offspring will be obligate heterozygotes (carriers) for the disease-causing mutation. Carrier testing is available on a clinical basis by PI typing (isoelectric focusing) or mutation analysis for sibs and offspring of affected individuals. Prenatal diagnosis for pregnancies at increased risk is possible by molecular genetic testing once the diagnosis has been confirmed in an affected family member.
Alpha1-antitrypsin deficiency (α1ATD, AATD) is suspected in individuals with evidence of pulmonary disease (i.e., emphysema, asthma, persistent airflow obstruction, and/or chronic bronchitis) and/or evidence of liver disease at any age, including obstructive jaundice in infancy. AATD is also observed rarely in individuals with Wegener granulomatosis and necrotizing panniculitis.
The diagnosis of AATD relies on the following:
Demonstration of low plasma concentration of alpha1-antitrypsin (AAT)
AND
Observation of a deficient variant of the protein AAT by protease inhibitor (PI) typing
OR
Detection by molecular genetic testing of mutations in both copies of SERPINA1, the gene encoding AAT
Normal. Range is 80%-120% of normal. Mean is 1.3 g/L (range: 1.06-1.58 g/L) [Cox et al 1991, Whicher et al 1994].
Adults with the PI SS genotype. The range is usually 12%-24% of normal (mean: 18%±5% of normal, or 0.23 g/L).
Children with the PI ZZ genotype and liver disease. The plasma concentration can be as high as 40% of normal [Moroz et al 1976].
Note: (1) The PI type should be determined in all samples in which the plasma concentration of AAT is below 50% of normal. (2) Other conditions associated with low plasma concentration of AAT include: respiratory distress syndrome in newborns, severe protein loss, terminal liver failure, and cystic fibrosis. (3) Because AAT is an acute-phase reactant, its plasma concentration can be elevated into the normal range in PI MZ heterozygotes. Up to fourfold increases are observed in inflammatory conditions, cancer, and liver disease. Pregnancy and estrogen therapy produce modest increases.
PI type is determined by polyacrylamide isoelectric focusing (PIEF) of serum using a narrow pH range and is available in many laboratories.
Note: Letters were originally used to designate the protein, anode to cathode, in isoelectric focusing [Fagerhol & Braend 1965]. PI alleles can also be designated as amino acid changes.
PI alleles
PI*M (standard allele nomenclature) is the most common allele in all populations described to date. Common subtypes of the M allele are designated M1, M2, M3, and so on.
PI*Z (p.E342K) is the most common deficiency allele.
PI*S (p.E264V):
Reaches polymorphic frequencies in some populations, particularly in Italy;
Is usually of clinical interest only when associated with a deficiency variant that decreases the plasma concentration of AAT to less than 40% of normal [Jeppsson & Franzen 1982];
Usually occurs with M allele as PI MS (~8% of the Caucasian population).
Other deficiency alleles include PI*Mmalton (p.F52del), PI*Siiyama (p.S53F). Those of the other deficiency alleles that are "null" alleles do not produce a detectable AAT protein.
Note: At least 20 rare deficiency alleles comprise about 5% of all deficiency alleles, the majority being PI*Z. A large number of AAT protein variants that are not clinically significant have also been identified.
PI types
PI MM. Observed in normal individuals with normal plasma concentration of AAT who are homozygous for the M allele
PI MZ. Slightly increased risk for decreased lung function among heterzygotes
PI SZ. Not usually associated with a high risk for liver or lung disease; higher risk of developing chronic obstructive pulmonary disease (COPD) among smokers
PI ZZ. Observed in individuals homozygous for the Z allele who have clinical disease and plasma concentration of AAT approximately 18% of normal
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Gene. AATD is caused by mutations in SERPINA1, the gene encoding alpha1-antitrypsin (AAT).
Clinical uses
Confirmatory diagnostic testing
Preimplantation genetic diagnosis
Clinical testing
Targeted mutation analysis. Ninety-five percent of AATD is caused by the presence of two Z alleles. PCR-based approaches have been developed for detection of Z and S mutations.
Sequence analysis. Sequence analysis detects rare and null alleles in SERPINA1 that are not detected by targeted mutation analysis.
Table 1 summarizes molecular genetic testing for this disorder.
| Test Method | Mutations Detected | Mutation Detection Frequency | Test Availability |
|---|---|---|---|
| Targeted mutation analysis | PI*Z, PI*S | 95% 1 | Clinical
 |
| Sequence analysis | SERPINA1 sequence variants | Unknown |
1. 95% of AATD results from presence of these variants. Targeted mutation analysis that is specific for detecting PI Z and S does not detect any of the rare deficiency alleles.
The diagnosis of AATD is based on: (1) the presence of abnormally low AAT plasma concentration and (2) determination of PI type by: (a) polyacrylamide isoelectric focusing (IEF) or (b) molecular genetic testing.
IEF is less costly than molecular genetic testing and uses serum both for measuring the serum concentration and for PI typing. A range of variants from normal to deficient (though not "null") can be observed in a single IEF assay, testing many samples in a single gel. Molecular genetic testing using targeted mutation analysis for PI*Z and PI*S does not detect any of the rare deficiency variants.
Molecular genetic testing may be performed if the results of the PI typing are ambiguous, e.g., when a rare deficiency allele is suspected but cannot be observed on IEF.
Sequence analysis is useful if targeted mutation analysis reveals only one disease-associated allele in an individual who meets diagnostic criteria for AATD; however, identification of both disease-associated alleles is not required for diagnosis.
Molecular genetic testing is useful for prenatal diagnosis when the specific deficiency allele is known.
Note: Liver biopsy is not specific and is not required for diagnosis.
No phenotype other than AATD is currently known to be associated with mutations in SERPINA1.
Alpha1-antitrypsin deficiency (α1ATD, AATD) can present with hepatic dysfunction in individuals from infancy to over age 50 years and with pulmonary disorders in individuals over age 20 years. Phenotypic expression varies within and between families.
Adult-onset lung disease. Chronic obstructive pulmonary disease (COPD), specifically emphysema, is the most common clinical manifestation of AATD. In adults, smoking is the major factor influencing the course of COPD. The onset of respiratory disease in smokers with AATD is between age 40 and 50 years. In non-smokers, the onset can be delayed to the sixth decade and is often associated with a normal life span.
Obstructive pulmonary disease typically presents with dyspnea, cough, and wheezing for an average of five years before the diagnosis is established. In individuals with emphysema, chest CT shows a symmetric decrease in peripheral vasculature that is most prominent in the lower lungs [Fujimoto et al 2002, Ley et al 2004]. In individuals with emphysema, changes in lung mechanics are observed, with apparent increase in lung volumes and expiratory flow rates, which can be attributed in part to loss of elastic recoil.
Some individuals present with symptoms of bronchial asthma or chronic bronchitis. Features of asthma are common in individuals with severe AATD and are important factors in the accelerated FEV1 decline seen in young smokers with AATD [Eden et al 2003].
Clinically asymptomatic individuals with AATD may have abnormalities in closing volume, nitrogen washout volume, and lung mechanics [Gadek & Crystal 1983, Burdon et al 1996, Cheung et al 1997].
Childhood-onset lung disease. Although reported, emphysema in children with AATD is extremely rare and may result from the coexistence of other unidentified genetic disorders affecting the lung [Cox & Talamo 1979].
Risk for lung disease in heterozygotes. PI MZ heterozygotes constitute 2%-5% of most populations.
Non-smokers with the PI MZ type may show slight differences in lung function from individuals with the PI MM type, but they rarely express clinical symptoms.
Smokers with the PI MZ type show impairment in lung function, reflecting a loss of elastic recoil; some may show clinical symptoms [Hersh et al 2004]. In general, loss in elastic recoil for a smoker with the PI MZ type is similar to that of a non-smoker with the PI ZZ type.
Slight abnormalities of lung function can be present without clinical symptoms.
PI MZ or PI MS heterozygotes do not have an increased risk of developing asthma.
Childhood-onset liver disease. The most common manifestation of AATD-associated liver disease is jaundice, with increased bilirubinemia and raised serum aminotransferase levels in the early days and months of life. Histopathologic features include intrahepatic cholestasis, varying degrees of hepatocellular injury, and moderate fibrosis with inflammatory cells in portal areas.
Liver abnormalities develop in only a portion of children with AATD. In a study of 200,000 Swedish children who were followed up after newborn screening for AATD, 18% of those with the PI ZZ type developed clinically recognized liver abnormalities and 2.4% developed liver cirrhosis with death in childhood [Sveger 1976, Sveger 1988]. Liver damage may progress slowly [Volpert et al 2000].
In a follow-up study of 44 children with AATD-associated liver disease initially manifest as cirrhosis or portal hypertension, outcomes ranged from liver transplantation in two, to relatively healthy lives up to 23 years after diagnosis in seven [Migliazza et al 2000].
The overall risk to an individual with PI ZZ of developing severe liver disease in childhood is generally low (~2%); the risk is higher among sibs of a child with the PI ZZ type and liver disease. When liver abnormalities in the proband are mild and resolve, the risk of liver disease in sibs with the PI ZZ type is about 13%. When liver disease in the proband is severe, the risk for severe liver disease in sibs with the PI ZZ type may be about 40% [Cox 2004].
It is not known why only a small proportion of children with early hyperbilirubinemia have continued liver destruction leading to cirrhosis.
PI MZ and PI SZ types are not associated with an increased risk for childhood liver disease, although elevated levels of liver enzymes that resolve have sometimes been observed. In a study of 58 heterozygous children showing signs of liver involvement during the first six months of life, follow-up indicated that almost all children had normal values of liver enzymes at age 12 months, five years, and ten years [Pittschieler 2002].
Adult-onset liver disease. Liver disease in adults, manifest as cirrhosis and fibrosis, is not necessarily associated with a history of neonatal hepatitis. The incidence of liver disease apparently increases with age and is higher in males. Liver inclusions may be responsible for the liver disease in adults. Destruction of the liver is rapid when onset occurs in adults.
Between 15% and 19% of individuals over age 50 years with the PI ZZ type develop cirrhosis. The risk of liver disease at age 20-40 years is about 2%; at age 41-50 years, it is about 4% [Cox & Smyth 1983].
Hepatocellular carcinoma (HCC) has been reported. Significantly elevated risk of developing HCC was observed only in males with PI ZZ, and was unrelated to the presence of hepatitis B or C infection [Elzouki & Eriksson 1996].
Liver pathology. Aggregation/polymerization of Z-type AAT, first recognized during protein purification and observed within the hepatic inclusions [Carrell & Lomas 2002], is thought to be the cause of the liver disease. AATD liver inclusions are visualized as bright pink globules of various sizes, using periodic acid-Schiff (PAS) stain following diastase treatment (PAS-D). The extent of inclusion formation varies considerably; the number and size of liver inclusions increases with age. Inclusions are not observed before age 12 weeks. In infants with AATD, inclusions may be fine and granular and difficult to identify in percutaneous liver biopsy specimens. They are also observed in bile duct epithelium [Cutz & Cox 1979] and now studied as a model.
Because liver inclusions indicate the presence of at least one PI Z allele, histologic examination of the liver cannot distinguish between heterozygotes and homozygotes for AATD.
Persons who do not produce any AAT (i.e., null allele homozygotes) have not been reported to have liver inclusions or liver disease, although the number of reported null allele homozygotes is small.
Risk for liver disease in heterozygotes seems to be low. Among individuals presenting with chronic liver failure, a greater number of PI type MZ heterozygotes (8.4%) were observed than were reported in the general population (2%-4%) [Graziadei et al 1998]. Another study found a slightly increased risk of chronic liver disease in PI MZ heterozygotes, based on the presence of Z deposits in liver biopsy samples [Fischer et al 2000].
Membranoproliferative glomerulonephritis (MPGN) may occur in individuals with AATD with liver disease, although the overall probability of an individual of PI type ZZ developing severe renal disease appears to be low. All of the children in whom MPGN was identified had severe liver disease, suggesting that the kidney abnormality was a consequence of liver disease [Strife et al 1983].
Increased tendency to severe RA in PI MZ heterozygotes can be explained as a consequence of a low amount of circulating protease inhibitor in the joint fluid to prevent leukocyte elastase, cathepsin G, and collagenase from attacking the structural proteins of joint cartilages [Cox & Huber 1980]. Several subsequent studies produced conflicting results, probably because of varying disease severity among the different series under study. Of 246 Swedish persons who are PI ZZ, 4.4% had rheumatoid arthritis and an additional 3% had significant joint pain [Larsson 1978].
The following are rarely associated with AATD:
Vascular disease can present as intracranial aneurysms, arterial fibromuscular dysplasia, and severe bleeding disorders [Cox 1994]. One study reported decreased rates of hypertension in PI ZZ homozygotes [Cox 1994, Dahl et al 2003].
Panniculitis, occurring rarely in PI ZZ homozygotes, can present as erythematous tender nodules mainly on the trunk and proximal extremities, with characteristic ulceration [McBean et al 2003].
Anterior uveitis, an immunologic inflammatory eye disease, has been reported to be associated with an increased frequency of Z heterozygotes [Fearnley et al 1988].
Systemic necrotizing vasculitis in 14 PI ZZ homozygotes, all of whom had skin involvement and either renal or joint involvement, was associated with high prevalence of emphysema and hepatic abnormalities [Mazodier et al 1996].
Wegener granulomatosis can involve respiratory tract or multiple organs and presents with the inflammation of small to medium vessels with associated granulomas [Barnett et al 1999, Lonardo et al 2002].
Individuals with the PI ZZ genotype have highly variable phenotypes (see Other findings); thus, additional genetic and environmental factors must be involved.
Liver involvement is associated mainly with PI ZZ genotype [DeMeo & Silverman 2004].
Other rare deficiency variants are also characterized by highly variable phenotypes.
The presence of a deficiency allele, predominantly Z, in homozygous form, can be associated with pulmonary or hepatic disease with various ages of onset, but the risk for disease does not appear to be appreciable.
The incidence and age of onset of adult lung disease is highly correlated with tobacco smoke and dust exposure. Passive smoking, particularly parental smoking, is also a risk factor.
The factors predisposing to liver manifestations are not known.
The original designations of PI types (F-fast, M-medium, S-slow) reflected gel mobility. Other variants were given additional alphabetical designations. Rare variants were named by place of origin of the proband. Current guidelines, using standard numerical sequence designations, can be used for increased precision.
In some publications, the term α1-protease inhibitor is used for AAT.
AATD is one of the most common metabolic disorders in the Caucasian population, occurring in about one in 5,000-7,000 individuals in North America and one in 1,500-3,000 in Scandinavians; AATD is present in lower frequencies in all racial subgroups worldwide [Campbell 2000, Miravitlles 2000].
Within Europe, the highest prevalence of the Z allele is observed in northern and western countries (mean gene frequency of 0.0153), gradually decreasing throughout Europe, with the lowest prevalence in eastern Europe (0.0092).
The frequency of the S allele is the highest in southern Europe (0.0564), decreasing in northern Europe (0.0176) [de Serres 2002, Luisetti & Seersholm 2004].
In a recent analysis of 75,390 individuals from Europe, the mean prevalence of PI ZZ type was one in 4,727; the highest frequency was found in Denmark (1:1,368) and the lowest frequency in Russia (1:86,065).
The mean European prevalence of PI SS was one in 934, with the highest in Hungary (1:21) and the lowest in Finland (1:18,566) [de Serres 2002, de Serres et al 2003b, Luisetti & Seersholm 2004].
AATD (PI ZZ type) is rare in Asian and black populations, except in those populations known to be highly heterogeneous, as in the United States [de Serres 2002, de Serres et al 2003a]. However, other rare deficiency variants occur in the Asian and black populations.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Lung disease. Signs of airflow limitation in alpha1-antitrypsin deficiency (α1ATD, AATD) can be similar to features of asthma or allergy. In a study of 1,052 individuals with AATD, features of astha were present in 21% and attacks of wheezing in 66% [Eden et al 2003]. The prevalence of AATD in persons with asthma or pulmonary emphysema does not differ from that found in the general population [Wencker et al 2002, Miravitlles et al 2003].
Liver disease. Other liver diseases that need to be considered are: chronic viral hepatitis, hereditary hemochromatosis (see HFE-Associated Hereditary Hemochromatosis, Juvenile Hereditary Hemochromatosis), Wilson disease, non-alcoholic steatohepatitis (NASH), and primary biliary cirrhosis.
In a study of 85 children with neonatal cholestasis, AATD was among the most common diagnoses (11/85); others were extrahepatic biliary atresia (30/85) and progressive familial intrahepatic cholestasis (11/85) (see Low Gamma-GT Familial Intrahepatic Cholestasis) [Fischler et al 2001a, Fischler et al 2001b].
Z allele frequency was also high (12%) in a group of 29 individuals with cholestatic jaundice and cirrhosis, when compared with controls (0.5%) [Lima et al 2001].
The presence of Z or S mutations in persons with cystic fibrosis confers a three- to sevenfold increased risk for CF-associated severe liver disease [Friedman et al 2001].
A deficiency of the related serpin alpha1-antichymotrypsin (SERPINA3) is reported to be associated with liver disease [Lindmark & Eriksson 1991].
Liver assessment. In individuals with manifestations of liver disease, liver biopsy for light microscopy and histochemistry is useful initially to determine the extent of liver disease and liver inclusions. However, liver function tests are usually adequate for subsequent monitoring of liver status.
Pulmonary assessment. Lung function measurements including spirometry, lung volumes, and diffusing capacity.
In alpha1-antitrypsin deficiency (α1ATD, AATD), lung density is a more sensitive indicator of lung disease progression than lung function measurements [Shaker et al 2004]. Lung density measurements by CT scan appear to show excellent sensitivity for early detection of pulmonary abnormalities [Stolk et al 2003].
Lung transplantation may be an appropriate option for individuals younger than age 60 years with end-stage lung disease (i.e., FEV1 below 30%) [Seersholm et al 1994, Trulock 1998]. However, despite apparent clinical improvement, five-year survival is no greater than for individuals who have not undergone lung transplantation.
Liver transplantation, the preferred surgical treatment for advanced liver disease, can provide a cure because the donor liver produces AAT [Francavilla et al 2000].
Panniculitis, a rarely associated disorder, has been alleviated with intravenous AAT. The lesions usually resolve spontaneously or after oral steroid therapy [Yesudian et al 2004]. In a severe case, immediate reduction of inflammation was achieved after administering human purified ATT [Chowdhury et al 2002].
Therapies to prevent FEV1 decline in individuals with AATD with pulmonary symptoms are the following:
Intravenous augmentation therapy. Regular infusion of purified AAT to augment deficient serum levels is used in some individuals; however, appropriately controlled trials have not been carried out [Gildea et al 2003]. Studies have demonstrated possible clinical efficacy for those with moderate lung damage. Recipients of augmentation therapy, particularly those with moderate degrees of airflow obstruction, have a somewhat slower rate of FEV1 decline.
Guidelines for its use have been reported [Abboud et al 2001, Society ATSER 2003, Abboud et al 2004, Stoller 2004]. Augmentation therapy has been recommended by the Canadian Thoracic Society for individuals with AATD whose FEV1 is 35%-50% of predicted, who have quit smoking, and who continue to show rapid decline in FEV1 despite optimal medical therapy [Abboud et al 2001].
Lifestyle. Expression of the disorder can be modified in asymptomatic individuals by lifestyle changes, including avoidance of smoking and occupations with exposure to environmental pollutants. Regular exercise and good nutrition are expected to be beneficial in maintaining lung health.
Vitamin E therapy improves liver function in infants with PI MZ and in children with cholestasis [Sokol et al 1986, Pittschieler 1991], and could be predicted to help prevent oxidative damage to the lungs.
Breast-feeding. The risk of childhood-onset liver disease in infants with PI ZZ who are breast-fed during the first month of life was reported to be reduced, but breast-feeding does not offer absolute protection against the development of severe liver disease [Sveger 1985].
Liver function should be evaluated periodically in all individuals with PI ZZ, including those who did not manifest childhood liver disease.
Smoking (both active and passive) is a risk factor for AATD.
Occupational hazards including exposure to environmental pollutants used in agriculture, mineral dust, gas, and fumes are an independent risk factor for impairment of lung function in older non-smoking PI ZZ individuals.
Inhaled administration of purified AAT can reconstitute the lower respiratory tract antitrypsin screen and potentially reduce inflammation [Hubbard & Crystal 1990]. Although several products have been developed for this therapy, the approach has not been evaluated in randomized, blinded efficacy trials [Sandhaus 2004, Abusriwil & Stockley 2006].
Synthetic inhibitors of human neutrophil elastase, administered intravenously and orally, could theoretically replace purified AAT in its function. Synthetic inhibitors of human neutrophil elastase have been used to treat cystic fibrosis, chronic bronchitis, and COPD without promising results. Trials in individuals with AATD have not been done [Sandhaus 2004].
Antioxidant therapy. Vitamins A, C, and E have been suggested in the treatment of AATD-related emphysema. The efficacy of such treatment has not been evaluated [Sandhaus 2004].
Synthetic chaperones and polymerization could potentially prevent intracellular polymerization of AAT leading to liver inclusions. Modest improvement in liver retention and increase in plasma concentrations of AAT was suggested after administration of 4-phenyl-butyric acid [Burrows et al 2000]. However, further studies have so far failed to demonstrate improvement [Teckman 2004]. Biochemical data on a peptide that specifically binds to Z AAT and inhibits polymerization are promising, but future cellular and animal studies are necessary [Mahadeva et al 2002, Parfrey et al 2004].
Gene therapy is aimed at introducing a normal gene into the cells and turning off production of the endogenous abnormal gene product. While cell culture and animal studies have been promising, the effectiveness of this approach in humans is still theoretical [Stecenko & Brigham 2003].
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Lung volume reduction surgery (LVRS) performed for persons with advanced non-AATD emphysema can improve lung function; individuals with higher preoperative FEV1 have a survival benefit [Fujimoto et al 2002]. However, in AATD-associated emphysema, the physiologic improvement is modest and offers only short-term benefits [Gelb et al 1999]. In a study of 12 individuals with AATD-related emphysema, lung function returned to baseline six to 12 months postoperatively but showed further deterioration 24 months postoperatively [Cassina et al 1998]. LVRS is therefore not recommended for individuals with AATD.
Transgenic/recombinant production of human AAT protein could solve the potential problems of limited supply of AAT purified from human plasma and transmission of infectious agents. However, clinical trials of transgenic/recombinant production of AAT in sheep and goats [Casolaro et al 1987, Wright et al 1991, Ziomek 1998] have been discontinued because of serious immunologic reactions in the lungs of recipients.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Alpha1-antitrypsin deficiency (α1ATD, AATD) is inherited in an autosomal recessive manner.
Parents of a proband
The parents of an individual with ATD have at least one disease-causing allele and are usually heterozygous (e.g., MZ, SZ); on occasion, a parent may be homozygous (ZZ).
Clinical disease is uncommon in heterozygotes; individuals who smoke and who have PI SZ have a slightly increased disease risk, although the majority are clinically unaffected.
Sibs of a proband
When both parents are carriers, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
When one parent is homozyhous and the other parent is a carrier, each sib has a 50% chance of having AATD and a 50% chance of being a carrier.
PI typing should be offered to all sibs.
Although the age of onset, severity, type of symptoms, or rate of progression of AATD cannot be predicted, some estimates are available on the risk to sibs of developing severe liver disease in infancy [Cox 2004)].
If the parents are carriers but have not had a child with severe liver disease, the risk to offspring of having AATD (25%) AND severe liver disease in childhood (13.6%) is less than 1% (0.64%).
If the proband died from severe liver disease in childhood, the risk to sibs of having AATD (25%) AND severe liver disease in childhood (40%) is 10%.
If the proband did not have severe liver disease in childhood or if the liver disease resolved, the risk to sibs of having AATD (25%) and liver disease (13%) is 3.3%.
Offspring of a proband
Unless an individual with AATD has children with a reproductive partner who is affected or a carrier, his/her offspring will be obligate heterozygotes (carriers) for the disease-causing mutation.
In populations with a high carrier frequency and/or a high rate of consanguinity, the reproductive partner of the proband may be affected or a carrier. Thus, the risk to offspring is most accurately determined after PI typing or molecular genetic testing of the proband's reproductive partner.
Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.
Carrier testing by PI typing (isoelectric focusing) or mutation analysis is available on a clinical basis for sibs and offspring of affected individuals. Measurement of AAT in serum is not reliable.
Family planning. The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See DNA Banking for a list of laboratories offering this service.
Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed. This testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression of the disorder. Of note, the risk for childhood liver disease is often low.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Because some individuals with AATD develop severe liver disease in the newborn period, and some of these children have a poor outcome, prenatal diagnosis may be of interest to some at-risk couples who have previously had a child with severe liver disease; the overall risk to subsequent offspring of developing severe liver disease is 10% [Cox 2004].
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified in an affected family member. For laboratories offering PGD, see
.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name |
|---|---|---|
| SERPINA1 | 14q32.1 | Alpha-1-antitrypsin |
Data are compiled from the following standard references: Gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
| 107400 | PROTEASE INHIBITOR 1; PI |
| Gene Symbol | Entrez Gene | HGMD |
|---|---|---|
| SERPINA1 | 5265 (MIM No. 107400) | SERPINA1 |
For a description of the genomic databases listed, click here.
Note: HGMD requires registration.
The basis for pulmonary disease in alpha1-antitrypsin deficiency (AATD) is a reduced inhibition of leukocyte elastase in the lung, resulting in excessive destruction of the elastin in the alveolae. Decades of research support this mechanism as causative. The adult-onset liver disease seen in individuals with AATD may result from damage caused by the accumulation of aggregated AAT in hepatocytes and bile ducts. The cause of progressive liver disease in infants and children with AATD is less clear. Early damage to bile ducts may be a destructive factor. Liver abnormalities in infants are noted in early weeks when deposits of AAT are minimal. Liver destruction proceeds, in a minority of infants, to cirrhosis, but the genetic and/or environmental factors have not been defined. Ineffective clearance by protein chaperones has been suggested as a factor [Kopito & Ron 200, Perlmutter 2002].
Normal allelic variants: SERPINA1 has five exons and a total length of 12.2 kb. There are two promoters, with one controlling expression in macrophaqes. More than 100 genetic variants of AAT, most of which have no disease associations, have been described.
Pathologic allelic variants: Ninety-five percent of AATD results from the presence of two Z alleles. At least 14 null alleles and at least 20 rare deficiency alleles, found in many populations, comprise the remaining 5% of all deficiency variants. PI*Mmalton, like the Z variant, aggregates in the liver and is one of the more prevalent variants of the 5%.
Normal gene product: Alpha1-antitrypsin (AAT) is a major serum protease inhibitor (PI), particularly important in inhibiting tissue elastase.
Abnormal gene product: The Z variant self-aggregates, other variants are more easily degraded, and others are not produced because of unstable mRNA. The null variants produce less than 2% of normal AAT [Brantly et al 1988, Cox & Billingsley 1989, Faber et al 1994].
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
Alpha-1 Advocacy Alliance
PO Box 202
103 Rapidan Church Lane
Wolftown VA 22748
Phone: 866-367-2122; 540-948-6777
Fax: 540-948-6763
Email: alpha1advocacyalliance@yahoo.com
www.alpha1advocacy.org
Alpha-1 Association
2937 SW 27 Avenue Suite 106
Miami FL 33133
Phone: 800-521-3025; 305-648-0088
Fax: 305-648-0089
Email: Info@alpha1.org
www.alpha1.org
Alpha-1 Canada
1638 Northway Avenue
Windsor N9B 3L9
Canada
Phone: 888-669-4583; 519-258-1444
Fax: 519-258-1614
Email: nfo@alpha1canada.ca
www.alpha1canada.ca
Alpha-1 Foundation
2937 SW 27th Avenue Suite 302
Miami FL 33133
Phone: 877-2 CURE A1 (877-228-7321); 305-567-9888
Fax: 305-567-1317
Email: lrodriguez@alphaone.org
www.alphaone.org
National Library of Medicine Genetics Home Reference
Apha-1 antitrypsin deficiency
NCBI Genes and Disease
Alpha -1-antitrypsin deficiency
American Liver Foundation
75 Maiden Lane Suite 603
New York NY 10038
Phone: 800-GO-LIVER (800-465-4837)
Fax: 212-483-8179
Email: info@liverfoundation.org
liverfoundation.org
Canadian Liver Foundation
2235 Sheppard Avenue East Suite 1500
Toronto M2J 5B5
Canada
Phone: 800-563-5483; 416-491-3353
Fax: 416-491-4952
Email: clf@liver.ca
www.liver.ca
Children Living with Inherited Metabolic Diseases (CLIMB)
Climb Building
176 Nantwich Road
Crewe CW2 6BG
United Kingdom
Phone: 0800 652 3181 (toll free)
Email: info.svcs@climb.org.uk
www.climb.org.uk
Children's Liver Disease Foundation
36 Great Charles Street
Birmingham B3 3JY
United Kingdom
Phone: 0121 212 3839
Fax: 0121 212 4300
Email: info@childliverdisease.org
www.childliverdisease.org
Alpha One International Registry (AIR)
Email: edwardc@aatdetection.com
www.aatregistry.org
Alpha-1 Canadian Registry
Toronto Hospital Western Division
Edith Cavell Wing Suite 4-011 399 Bathurst Street
Toronto M5T 2S8
Canada
Phone: 800-352-8186; 416-603-5020
Fax: 416-603-5020
Email: paterson@alpha1canadianregistry.com
www.alpha1canadianregistry.com
Cholestatic Liver Disease Consortium Registry (CLiC)
The Children's Hospital
Section of Pediatric Gastroenterology/Hepatology/Nutrition
1056 E 19th Av B290
Denver CO 80218
Phone: 303-837-2598
Fax: 303-861-6104
Email: hines.joan@tchden.org
CLiC Registry
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
6 February 2008 (cd) Revision: sequence analysis available on a clinical basis
27 October 2006 (me) Review posted to live Web site
15 February 2005 (mb) Original submission
